GATA4 as a Modulator of Aortic Root Sensitivity to Mechanochemical Disruptions Caused by an Aneurysm-causing Mutation

项目概要 主动脉瘤是局部扩张，容易导致血管夹层或破裂，这两种情况都是 与高死亡率相关。 Loeys-Dietz 综合征 (LDS) 是一种遗传性动脉瘤疾病，由 损害但不完全破坏 TGF-β 信号传导的突变。 LDS 患者有很强的倾向 主动脉根部疾病，尽管在这种情况下突变的基因普遍表达 整个脉管系统。这种局部漏洞背后的机制仍不清楚。在这个 建议，我将检验以下假设：平滑肌细胞中表达的内在因子存在于 主动脉根部使它们更容易受到主动脉机械化学破坏的影响 LDS 突变。具体来说，我将研究 Gata4 在血管平滑细胞亚群中的内在表达是否 当稳态抑制机制依赖于肌肉细胞时，肌肉细胞会促使这些细胞上调 GATA4 这些细胞和细胞外基质之间的适当接触失败。我将得到我的赞助商 Dr. 的支持。 MacFarlane 和共同发起人 Dietz 博士，以完成以下目标。在目标 1 中，我将揭示 LDS 如何 突变影响主动脉细胞外基质结构和粘着斑下游信号传导并检查 药理学干扰这些途径对动脉瘤发病机制的影响。在目标 2 中，我将 通过考察产后效应阐明GATA4在主动脉根部动脉瘤发病机制中的作用 平滑肌特异性删除 Gata4 对主动脉根部扩张的影响。在我的合作者 Dr. 的帮助下 鹿儿原先生是空间转录组学方面的专家，我也将学习使用这项尖端技术并 相关的计算工具来绘制沿主动脉长度的转录异质性梯度。我 将进一步发展我作为独立研究员的技能并增强我在心血管方面的专业知识 通过完成重点课程并定期参加科学会议并在会上发表演讲来学习生物学。至 提高我的科学交流技能，我将寻求更多的指导和教学机会， 包括在约翰霍普金斯大学教授本科遗传学课程。通过完成这个 提案，我将获得获得博士后职位所需的经验和技能，并且 最终在心血管研究领域建立了独立的学术生涯。

PROJECT SUMMARY Aortic aneurysms are localized dilations that predispose the vessel to dissection or rupture, both of which are associated with high mortality. Loeys-Dietz Syndrome (LDS) is a hereditary aneurysm disorder caused by mutations that impair, but do not fully disrupt, TGF-β signaling. LDS patients have a strong predisposition for disease in the aortic root even though the genes that are mutated in this condition are ubiquitously expressed throughout the vasculature. The mechanisms that underlie this localized vulnerability remain unclear. In this proposal, I will test the hypothesis that intrinsic factors expressed in smooth muscle cells present in the aortic root render them more susceptible to the mechanochemical disruptions of the aorta caused by LDS mutations. Specifically, I will investigate if intrinsic expression of Gata4 in a subset of vascular smooth muscle cells primes these cells to upregulate GATA4 when homeostatic inhibitory mechanisms that depend on proper contacts between these cells and the extracellular matrix fail. I will be supported by my sponsor, Dr. MacFarlane, and co-sponsor, Dr. Dietz, to complete the following aims. In Aim 1, I will uncover how LDS mutations affect aortic extracellular matrix structure and signaling downstream of focal adhesions and examine the effect of pharmacological interference with these pathways on aneurysm pathogenesis. In Aim 2, I will clarify the role of GATA4 in the pathogenesis of aortic root aneurysm by examining the effect of postnatal smooth muscle specific deletion of Gata4 on aortic root dilation. With the help of my collaborator, Dr. Kagohara, who is an expert in spatial transcriptomics, I will also learn use this cutting-edge technology and related computational tools to map the gradient of transcriptional heterogeneity along the length of the aorta. I will further develop my skills as an independent researcher and enhance my expertise in cardiovascular biology by completing focused coursework and regularly attending and presenting at scientific conferences. To improve my skills in scientific communication, I will seek out additional mentoring and teaching opportunities, including teaching an undergraduate genetics course at Johns Hopkins University. By completing this proposal, I will acquire the experience and skills necessary to attain a position as a postdoctoral fellow, and ultimately establish an independent academic career in cardiovascular research.